Preparation method of Bainapenem
Through a simplified three-step reaction method, using specific raw materials for condensation and MAP combination, the synthesis efficiency and yield of phenanpenem was successfully improved, and the problems of complex synthesis routes and low yields in the existing technology were solved, which was suitable for industrial production.
Patent Information
- Application Number
- CN202311645161.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-04
- Publication Date
- 2025-06-06
AI Technical Summary
The existing methods of synthesis of carbapenem antibiotics are complex and have many reaction steps, which leads to low yield and is not suitable for industrial production.
5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one and sulfamemillone acetate were used as starting materials. The synthesis route was simplified and the yield was improved through three-step reactions such as condensation reaction, MAP binding and deprotection.
It has achieved efficient synthesis of phenanpenem, simplified the process flow, improved yield, was suitable for industrial production, and ensured the safety and efficacy of the product.
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Figure CN120097983A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a synthesis method of benapenem, belonging to the preparation of carbapenem antibiotics. Background Art
[0002] Carbapenem antibiotics are a class of β-lactam antibiotics with the broadest antibacterial spectrum and the strongest antibacterial activity. They have bactericidal effects on many bacteria in vitro, including Gram-positive and Gram-negative aerobic and anaerobic bacteria; in addition, carbapenems are stable to almost all β-lactamases, including AmpC β-lactamases and extended-spectrum β-lactamases (ESBLs).
[0003] Benapenem is a carbapenem antibiotic with a novel structure and a long half-life. Studies have shown that Benapenem has higher safety and better pharmacodynamics and pharmacokinetic characteristics, and its quality is controllable. Its structural formula is shown below:
[0004] Summary of the invention:
[0005] The present invention aims to provide a preparation method of benapenem, which has a short synthesis route, and only requires three steps of reaction to obtain the target product, and the yield is significantly improved compared with other similar products. The reaction conditions are mild and controllable, the operation process is safe and reliable, and it is suitable for industrial production.
[0006] The preparation method of benapenem provided by the present invention is characterized by: using 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one and mafenide acetate as starting materials, performing a condensation reaction to form an intermediate compound 3, combining compound 3 with MAP to form an intermediate compound 5, and deprotecting the intermediate compound 5 to obtain benapenem.
[0007] MAP:
[0008]
[0009] Furthermore, the preparation method of Benapenem provided by the present invention is also characterized in that:
[0010] The specific process of the above condensation reaction is: under the protection of protective gas, at a reaction temperature of 10-50° C., to a mixed solution of 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one and sulfamethoxazole acetate, an organic base is added dropwise and reacted for 0.5-2 hours.
[0011] Furthermore, the preparation method of Benapenem provided by the present invention is also characterized in that:
[0012] The molar ratio of the above 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one to mafenide acetate is 1:0.9-1.1.
[0013] Furthermore, the preparation method of Benapenem provided by the present invention is also characterized in that:
[0014] The mixture of the intermediate compound 3 and MAP was cooled to -20-5°C, and an organic base was added dropwise under protective gas. After the addition was completed, the mixture was kept at -20-5°C for 2 hours.
[0015] Furthermore, the preparation method of Benapenem provided by the present invention is also characterized in that:
[0016] The molar ratio of the above-mentioned mafenide acetate to MAP is 1:0.9-1.1.
[0017] Furthermore, the preparation method of Benapenem provided by the present invention is also characterized in that:
[0018] The purification process of the intermediate compound 5 is as follows: add an ester solvent to the reaction solution, wash with water and saturated sodium bicarbonate aqueous solution in sequence, dry the organic layer, add alkane, concentrate under reduced pressure to 1 / 2-1 / 3 of the volume, and then stir to crystallize.
[0019] Furthermore, the preparation method of Benapenem provided by the present invention is also characterized in that:
[0020] The above-mentioned organic base is selected from amines.
[0021] Furthermore, the preparation method of Benapenem provided by the present invention is also characterized in that:
[0022] An aqueous solution of an inorganic base is added to the solution of the intermediate compound 5. After the two solutions are mixed, 5-10% palladium carbon is added, hydrogen is introduced, the pressure is increased to 3.0-4.0 MPa, the temperature is increased to 10-20° C., and stirring is performed until the reaction is complete.
[0023] Furthermore, the preparation method of Benapenem provided by the present invention is also characterized in that:
[0024] The reaction product is purified by filtration, extraction, adjusting the pH to 4.0-6.0 and then crystallizing. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 , the spectrum of compound 5 in Example 3;
[0026] Figure 2 , the spectrum of the target product of Example 3. DETAILED DESCRIPTION
[0027] The preparation method of Benapenem in this embodiment uses 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one and mafenide acetate as starting materials, and performs a condensation reaction to form an intermediate compound 3, compound 3 combines with MAP to form an intermediate compound 5, and intermediate compound 5 is deprotected to obtain Benapenem. The specific reaction equation is as follows:
[0028]
[0029] The reaction can be achieved when the molar ratio of 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one to mafenide acetate is 1:0.9-1.1; and the molar ratio of mafenide acetate to MAP is 1:0.9-1.1.
[0030] The specific process of the condensation reaction is: under the protection of protective gas, at a reaction temperature of 10-50° C., an organic base is added dropwise to a mixture of 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one and sulfamethoxazole acetate, and then reacted for 0.5-2 hours. When the reaction temperature is too low, the reaction hardly occurs, and when the reaction temperature is too high, too many side reactions occur.
[0031] The mixture of intermediate compound 3 and MAP was cooled to -20-5°C, and an organic base was added dropwise under protective gas. After the addition, the mixture was kept at -20-5°C for 2 hours. When the reaction temperature is too low, the reaction is slow and needs to be delayed. When the reaction temperature is too high, there are too many side reactions.
[0032] The purification process of the intermediate compound 5 is as follows: add an ester solvent to the reaction solution, wash with water and saturated sodium bicarbonate aqueous solution in sequence, dry the organic layer, add alkane, concentrate under reduced pressure to 1 / 3 of the volume, and then stir to crystallize.
[0033] An aqueous solution of an inorganic base is added to the solution of the intermediate compound 5. After the two solutions are mixed, 5-10% palladium carbon is added, hydrogen is introduced, the pressure is increased to 3.0-4.0 MPa, the temperature is increased to 10-20° C., and stirring is performed until the reaction is complete.
[0034] The optimal reaction conditions are as follows:
[0035] Example 1
[0036] Compound (1) (10 g, 0.033 mol) and compound (2) (7.6 g, 0.031 mol) were dissolved in acetonitrile (60 g) and heated to 30-40° C. Triethylamine (3.25 g) was added dropwise under nitrogen protection. After the addition, the mixture was reacted at 40° C. for 1 h and filtered to obtain compound (3).
[0037] All the above compounds (3) and compound (4) (17 g, 0.029 mol) were added to N,N-dimethylformamide (46 g), cooled to -10-0°C, and triethylamine (3.25 g) was added dropwise under nitrogen protection. After the addition, the mixture was kept warm for 2 hours. After the reaction was completed, the resulting reaction solution was added dropwise to water to precipitate compound (5), which was filtered and dried to obtain 18.7 g of compound (5) with a purity of 93.1% and a yield of 89.75%, based on compound (2).
[0038] Compound (5) (5.0 g, 5.96 mmol) was dissolved in tetrahydrofuran (50 g), sodium bicarbonate (1 g) was added to water (25 g), the two solutions were mixed and placed in a 250 ml hydrogenation kettle with 10% palladium carbon (1 g on dry basis), hydrogen was introduced, the pressure was increased to 4.0 MPa, the temperature was raised to 10-20°C, and the reaction was stirred until the reaction was complete. The reaction solution was filtered and the aqueous phase solution was separated, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to a pH value of about 4.0-6.0 with hydrochloric acid, and a white solid was precipitated, which was filtered, rinsed with anhydrous ethanol, and dried in vacuo to obtain 2.4 g of the finished product of Benapenem. The purity was 92.4%, and the yield was 61.88%.
[0039] Example 2
[0040] Compound (1) (10 g, 0.033 mol) and compound (2) (7.6 g, 0.031 mol) were dissolved in acetonitrile (60 g) and heated to 30-40° C. Triethylamine (3.25 g) was added dropwise under nitrogen protection. After the addition, the mixture was reacted at 40° C. for 1 h and filtered to obtain compound (3).
[0041] All the above compounds (3) and compound (4) (17 g, 0.029 mol) were added to N,N-dimethylformamide (46 g), cooled to -10-0°C, and triethylamine (3.25 g) was added dropwise under nitrogen protection. After the addition, the mixture was kept warm for 2 h. After the reaction was completed, ethyl acetate (50 g) was added to the reaction solution. The mixture was washed with water and 50 ml of saturated sodium bicarbonate aqueous solution in turn, and the organic layer was dried over anhydrous sodium sulfate. N-hexane (20 g) was added to the organic layer, and the organic layer was finally concentrated to 1 / 3 of its volume at 30°C under reduced pressure and then stirred for crystallization for 2 h. After filtration and drying, 17.71 g of compound (5) was obtained, with a purity of 96.3% and a yield of 84.99%, based on compound (2).
[0042] Compound (5) (5.0 g, 5.96 mmol) was dissolved in tetrahydrofuran (50 g), sodium bicarbonate (1 g) was added to water (25 g), the two solutions were mixed and placed in a 250 ml hydrogenation kettle with 10% palladium carbon (1 g on dry basis), hydrogen was introduced, the pressure was increased to 4.0 MPa, the temperature was raised to 10-20°C, and the reaction was stirred until the reaction was complete. The reaction solution was filtered and the aqueous phase solution was separated, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to a pH value of about 4.0-6.0 with hydrochloric acid, and a white solid was precipitated, which was filtered, rinsed with anhydrous ethanol, and dried in vacuo. 2.46 g of the finished product of Benapenem was obtained. The purity was 94.4% and the yield was 63.43%.
[0043] Example 3
[0044] Compound (1) (10 g, 0.033 mol) and compound (2) (7.6 g, 0.031 mol) were dissolved in acetonitrile (60 g) and heated to 30-40° C. Triethylamine (3.25 g) was added dropwise under nitrogen protection. After the addition, the mixture was reacted at 40° C. for 1 h and filtered to obtain compound (3).
[0045] All the above compounds (3) and compound (4) (17 g, 0.029 mol) were added to N,N-dimethylformamide (46 g), cooled to -10-0°C, and triethylamine (3.25 g) was added dropwise under nitrogen protection. After the addition was completed, the mixture was kept warm for 2 h. After the reaction was completed, ethyl acetate (50 g) was added to the reaction solution. The mixture was washed with water and 50 ml of saturated sodium bicarbonate aqueous solution in turn, and the organic layer was dried over anhydrous sodium sulfate. Finally, the ethyl acetate layer was concentrated to half its volume under reduced pressure at 30°C and then stirred for crystallization for 2 h. Filtered and dried to obtain 16.83 g of compound (5) with a purity of 99.6% and a yield of 80.77%, based on compound (2).
[0046] Compound (5) (5.0 g, 5.96 mmol) was dissolved in tetrahydrofuran (50 g), sodium bicarbonate (1 g) was added to water (25 g), the two solutions were mixed and placed in a 250 ml hydrogenation kettle with 10% palladium carbon (1 g on dry basis), hydrogen was introduced, the pressure was increased to 4.0 MPa, the temperature was raised to 10-20°C, and the reaction was stirred until the reaction was complete. The reaction solution was filtered and the aqueous phase solution was separated, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to a pH value of about 4.0-6.0 with hydrochloric acid, and a white solid was precipitated, which was filtered, rinsed with anhydrous ethanol, and dried in vacuo to obtain 2.47 g of the finished product of Benapenem. The purity was 97.4%, and the yield was 63.69%.
Claims
1. A method for preparing benapenem, Features: Using 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one and mafenide acetate as starting materials, a condensation reaction is carried out to form an intermediate compound 3, compound 3 is combined with MAP to form an intermediate compound 5, and the intermediate compound 5 is deprotected to obtain benapenem.
2. The method for preparing benapenem according to claim 1, Features: The specific process of the condensation reaction is: under the protection of protective gas, at a reaction temperature of 10-50° C., to a mixed solution of 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one and mafenide acetate, an organic base is added dropwise and reacted for 0.5-2 hours.
3. The method for preparing benapenem according to claim 1, Features: The molar ratio of the 5-N-(4-nitrobenzyloxycarbonyl)-2-thia-5-azabicyclo[2.2.1]heptan-3-one to mafenide acetate is 1:0.9-1.
1.
4. The method for preparing benapenem according to claim 1, Features: The mixture of the intermediate compound 3 and MAP was cooled to -20-5°C, and an organic base was added dropwise under protective gas. After the addition was completed, the mixture was kept at -20-5°C for 2 hours.
5. The method for preparing benapenem according to claim 1, Features: The molar ratio of mafenide acetate to MAP is 1:0.9-1.
1.
6. The method for preparing benapenem as claimed in claim 1 or 4, Features: The organic base is selected from amines.
7. The method for preparing benapenem as claimed in claim 1, Features: The purification process of the intermediate compound 5 is as follows: add an ester solvent to the reaction solution, wash with water and saturated sodium bicarbonate aqueous solution in sequence, dry the organic layer, add alkane, concentrate under reduced pressure to 1 / 2-1 / 3 of the volume, and then stir to crystallize.
8. The method for preparing benapenem according to claim 1, Features: An aqueous solution of an inorganic base is added to the solution of the intermediate compound 5. After the two solutions are mixed, 5-10% palladium carbon is added, hydrogen is introduced, the pressure is increased to 3.0-4.0 MPa, the temperature is increased to 10-20° C., and stirring is performed until the reaction is complete.
9. The method for preparing benapenem as claimed in claim 8, Features: The reaction product is purified by filtration, extraction, adjusting the pH to 4.0-6.0 and then crystallizing.